Microwave-assisted synthesis of β-lactams and cyclo-β-dipeptides

Article abstract of DOI:10.1002/hlca.201200449

Different cyclo-β-dipeptides were prepared from corresponding N-substituted β-alanine derivatives under mild conditions using PhPOCl ₂ as activating agent in benzene and Et₃N as base. To evaluate β³-substituent influence,

Full text of DOI:10.1002/hlca.201200449

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Helvetica Chimica Acta – Vol. 95 (2012)
Microwave-Assisted Synthesis of b-Lactams and Cyclo-b-dipeptides
by Luis G. Herna´ndez-Va´zqueza), Marco A. Leyvab), Alejandro J. Metta-Magan˜ac),
Jaime Escalante*a)
a
´
) Centro de Investigaciones Quꢀmicas, Universidad Autonoma del Estado de Morelos, Av. Universidad
´
No. 1001, Col. Chamilpa, C.P. 62209, Cuernavaca, Mor., Mexico (e-mail: jaime@ciq.uaem.mx)
b
´
) Cinvestav-I.P.N., Departamento de Quꢀmica, Av. Instituto Politecnico Nacional 2508,
´
´
Col. San Pedro Zacatenco, C.P. 07000, Mexico D.F., Mexico
c) Department of Chemistry, University of Texas at El Paso, El Paso, TX 79968-0513, USA
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
Different cyclo-b-dipeptides were prepared from corresponding N-substituted b-alanine derivatives
under mild conditions using PhPOCl2 as activating agent in benzene and Et3N as base. To evaluate b3-
substituent influence, the amino acids 7 – 26 were synthesized, and a b-lactam formation reaction was
carried out instead of cyclo-b-dipeptide formation. The crystal structures of three derivatives of cyclo-b-
peptides and one b-lactam are presented.
1. Introduction. – In the last few decades, several methods have been developed for
enantioselective preparation of b-amino acids [1] due to their biological properties [2],
and their application in the synthesis of b-lactams [3] and b-peptides [4], which have
been shown to possess biological activities [5], and also because many b-amino acids
have been identified as building blocks in natural occurring peptides and antibiotics
mainly in plants [6a], microorganisms [6b][6c], and some mammalians [6d].
After the discovery of penicillin by Alexander Fleming, numerous reviews on
chemistry and biology of b-lactam antibiotics have been published. The key feature of
this kind of antibiotics is the b-lactam ring, and because of the growing bacterial
resistance [7] due to unconscious use of antibiotics, demand for more potent analogs is
increasing. To achieve this goal, a wide range of synthetic methods to form the b-lactam
ring, i.e., the final step, have been developed [3][8].
On the other hand, b-peptides have shown to possess interesting properties such as
the ability to fold into stable secondary structures [9]. They also exhibit proteolytic
stability against enzymes [10], which is due to lack of recognition by the peptidase [11],
even though environmental microbial samples have been shown to use b-peptides as
nitrogen and carbon source [5b][12]. To increase stability against certain peptidases in
some peptides, an a-amino acid residue was replaced by a b-amino acid [13]. Due these
properties, b-peptidic drugs could be synthesized and would probably have an excellent
bioavailability and long-term activity. Moreover, cyclo-b-peptides can adopt, in solid
state, tubular structures [14] of pleated-sheet-type H-bonds, which have potential
application to promote ion-selective channel transport [14b][15]; also they have been
ꢁ 2012 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 95 (2012)
2219
found to mimic b-peptide hormones as the cyclo-b-tetrapeptide (b-HPhe-b-HThr-b-
HLys-b-HTrp) [16], with an affinity for human somatostatin receptors. Furthermore,
cyclo-b-tripeptides [17] have been synthesized, and successful growth against human
cancer cell lines were carried out.
We found that the more versatile way to prepare either b-lactams or cyclo-b-
dipeptides is activation of the C¼O group with an organophosphorus reagent [18] or
using Mukaiyamaꢃs reagent [3b], depending upon the solvent used. With phenyl-
phosphonic dichloride, PhPOCl2, the reaction follows two possible pathways depend-
ing on the b-substituent: in Pathway A, an intramolecular reaction occurs to form the b-
lactam, whereas, in Pathway B, a cyclic bis-amide is formed through an intramolecular
amide bond-formation in the intermediate linear b-peptide1) (Scheme 1).
Scheme 1
2. Results and Discussion. – 2.1. Preparations of Cyclo-b-dipeptides. For comparison
with microwave (MW)-assisted synthesis, cyclo-b-dipeptide 2A was prepared first by
conventional heating as reported in [18] (Scheme 2). After purification, a crystalline
solid was obtained (37% yield).
Scheme 2
We performed the same reaction by using MWs (Scheme 3), which have been
established as auxiliaries in organic synthesis by decreasing reaction times, increasing
yields, and even enhancing product purities [19]. Several experiments were carried out
under different conditions; the results are compiled in Table 1.
Several combinations of R1 and R2 were examined.
1
)

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 3
Table 1. Microwave-Assisted Formation of Cyclo-b-dipeptide 2A
Entry Volume [ml] Concentration [m] Power [W] PhPOCl2 [equiv.] Time [min] Yield [%]
2Aa) 2Ba)
1
2
3
4
5
6
7
8
9
80
40
40
40
20
80
40
20
10
0.0125
0.025
0.025
0.025
0.05
0.0125
0.025
0.05
90
130
130
130
130
130
130
130
130
1.5
1.5
1.5
1.5
1.5
0.5
0.5
0.5
0.5
120
60
30
15
30
30
30
30
30
37
18
30
16
16
27
27
23
24
–
–
–
–
9
traceb)
8
11
10
0.1
a) Yield after column chromatography. b) Detected by TLC.
Entry 1 indicates that using microwaves gives cyclo-b-dipeptide in yields compa-
rable to those reported in the literature [18][20], but with a considerable reduction in
the reaction time and solvent volume used. Also good yields of cyclo-b-dipeptide are
obtained by increasing the concentration and the MW accompanied by a furthermore
reduction in the reaction time (Entries 2 – 4).
Surprisingly, at a higher concentration (Entry 5), b-lactam 2B is formed, which was
not isolated by the conventional heating [18]. In Fig. 1, the differences between the
1H-NMR spectra of 2A and 2B are depicted. Decreasing the number of equiv. of
PhPOCl2 favored b-lactam formation (Entries 6 – 9). Entry 6 indicates that decreasing
PhPOCl2 equivalents gave at least traces of b-lactam at higher dilutions. According to
our criteria, the best conditions with respect to time, yield, and volume relations for the
preparation of the cyclo-b-dipeptide 2A are those of Entry 3 which are used in the
following experiments.
Once the optimal reaction conditions were established (Entry 3), reactions starting
from amino acids 3 and 4 were carried out to form cyclo-b-dipeptides 5A and 6A
(Scheme 4 and Table 2), respectively.
After purification by column chromatography, both compounds were obtained, and
their crystal structures were determined (Figs. 2 and 3). In solid state, both adopt a
twisted boat conformation with N-substituents in pseudo-axial orientations which is the
preferred conformation [18][21][22]. Although the CH2 H-atoms are partially
eclipsed, this is avoided by the slightly twisted boat conformation and is favored,
because Prelog strain (i.e., transannular strain) is null due to the presence of amide
group.

Helvetica Chimica Acta – Vol. 95 (2012)
2221
1
Fig. 1. Comparison of H-NMR spectra of cyclo-b-dipeptide 2A and b-lactam 2B. a-N- and benzylic H-
atom signals are shifted to higher field in b-lactam. If only NMR spectrum of either cyclo-b-dipeptide or
b-lactam is available, IR serves for identification.
Scheme 4
Table 2. Cyclo-b-dipeptides 5A and 6A from Amino Acids 3 and 4, Respectively
Entry
Starting material
R
Product
Yield [%]
IR (C¼O) [cmꢀ1
1641
1637
]
1
2
3
4
tBu
cHex
5A
6A
25
28
2.2. Preparation of b-Lactams. Amino acids 7 – 26 were prepared to evaluate the b3-
substituent effect in cyclo-b-dipeptide formation. Interestingly, no cyclo-b-dipeptide
formation was observed; instead, intramolecular reactions occured to form b-lactams
(Scheme 5 and Table 3).

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Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 2. Solid-state conformation of cyclo-b-dipeptide 5A2). The thermal ellipsoids are drawn at 50%
probability level with ORTEP and rendered using POV-Ray.
Fig. 3. Solid-state conformation of cyclo-b-dipeptide 6A2). The thermal ellipsoids are drawn at 50%
probability level with ORTEP and rendered using POV-Ray.
Scheme 5
Outstanding features of Table 3: i) The bulkier R1 becomes, the higher yield is
obtained (higher yields were achieved with R1 ¼ tBu (Entries 8 and 9) also high yields
were detected with R1 ¼ cHex (¼cyclohexyl; Entries 12 and 15)). ii) It seems that R2
has little effect on the yield when R1 ¼ Me (Entries 1 – 5), but bulky R2 lowers the yield
2
)
CCDC-894799 – 894802 contain the supplementary crystallographic data for this article. These data
can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 95 (2012)
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Table 3. b-Lactams 27B – 46B from Amino Acids 7 – 26, Respectively
Entry
Raw material
R1
R2
Product
Yield [%]
IR (C¼O) [cmꢀ1
]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
7
8
9
Me
Me
Me
Me
Bu
27B
28B
29B
30B
31B
32B
33B
34B
35B
36B
37B
38B
39B
40B
41A
41B
42B
43B
44B
45B
46B
65
64
65
55
69
86
65
70
90
53
76
81
56
64
trace
72
18
62
78
52
50
1736
1738
1737
1737
1730
1725
1744
1725
1745
1740
1742
1742
1753
1739
1628
1749
1753
1753
1629
1751
1751
i-Bu
tBu
cHex
Ph
10
11
12
13
14
15
16
17
18
19
20
21
21
22
23
24
25
26
Me
tBu
Bu
tBu
i-Bu
tBu
cHex
Ph
tBu
tBu
tBu
cHex
cHex
cHex
cHex
cHex
cHex
Ph
Ph
Ph
Ph
Ph
Bu
i-Bu
tBu
cHex
Ph
Ph
Bu
i-Bu
tBu
cHex
Ph
with R1 ¼ Ph (Entry 18). iii) This b-lactam formation can be interpreted as a related
phenomenon to ThorpeꢀIngold effect [23], where the substituents R1 and R2 tend to
bring N-atom closer to C¼O group the bulkier they are, favoring intramolecular
reaction.
Fig. 4. Solid-state conformation of cyclo-b-dipeptide 41A2). The thermal ellipsoids are drawn at 25%
probability level with ORTEP and rendered using POV-Ray.

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Helvetica Chimica Acta – Vol. 95 (2012)
Interestingly, it was possible to obtain the cyclo-b-dipeptide 41A from amino acid
21. A single crystal was obtained, and the crystal structure (Fig. 4) revealed that it
adopts a twisted boat conformation, with N-substituents in pseudo-axial orientations
and ring substituents occupying pseudo-equatorial positions. Furthermore, ring
substituents slightly decrease distances between amide N-atom and C¼O C-atom
across the ring, allowing an intramolecular electrostatic interaction.
Furthermore, it was deduced from the crystal structure of b-lactam 34B (Fig. 5) that
it has a planar ring conformation, where the N(1)ꢀC(5) bond is also in the same plane
of the ring as expected for an amide. This finding was also supported by the bond length
N(1)ꢀC(2), which is slightly shorter than NꢀC distance (1.47 ꢄ); this behavior is also
observed in the cyclo-b-dipeptides 5A, 6A, and 47A due to the tendency of the N-atom
to be in resonance with C¼O group, leading to a slightly longer C¼O bond.
Fig. 5. Solid-state conformation of b-lactam 34B2). The thermal ellipsoids are drawn at 50% probability
level with ORTEP and rendered using POV-Ray.
Additionally, several experiments were carried out (see Table 4) using Mukaiya-
maꢃs reagent to confirm that compounds 31B and 41B were in fact b-lactams. This,
because i) amino acid 11 was reported to form a cyclo-b-dipeptide by conventional
heating [18], and the IR spectrum of the product matches that of a b-lactam; ii) amino
acid 21 forms a cyclo-b-dipeptide (Fig. 4), which would not be formed by this method;
and iii) we wanted to prepare b-lactams from compounds 3 and 4 to compare their
properties with those of cyclo-b-dipeptides 5A and 6A.

Helvetica Chimica Acta – Vol. 95 (2012)
2225
The reactions were carried out with 1.0 mmol of amino acid (Table 4) in 40 ml of
MeCN, 1.1 mmol of 2-chloro-1-methylpyridinium iodide, and 2.2 mmol of Et3N.
Reaction mixture was exposed to MWs (Scheme 6).
Scheme 6
Table 4. b-Lactams Obtained Using 2-Chloro-1-methylpiridium Iodide
Entry Starting material Product Solvent 2-ClC5H4NþMe · Iꢀ [equiv.] Time [min] Yield [%]
A
B
1
2
3
4
5
6
7
8
1
1
1
3
4
11
21
24
2B
MeCN 1.1
10
30
30
10
10
10
10
10
–
62
31
22
64
48
74
87
46
2A, 2B C6H6
2A, 2B MeCN
5B
6B
31B
41B
44B
1.1
12
17
–
–
–
c
)
MeCN 1.1
MeCN 1.1
MeCN 1.1
MeCN 1.1
MeCN 1.1
–
–
c) PhPOCl2 was used.
The b-lactams 5B and 6B also have slightly similar 1H-NMR spectra as their cyclo-
b-dipeptide counterparts. As in the case of 2A and 2B, signals of both pairs of CH2 H-
atom in a-position to the N-atom are shifted to higher fields in b-lactams. For 31B, 41B,
and 44B, 1H- and 13C-NMR, IR, and MS (FABþ) data match those of the compounds
obtained, when PhPOCl2 was used. Crystals from 41A could not be obtained, since the
cyclo-b-dipeptide was only obtained when PhPOCl2 was used as activating agent.
Noteworthy results collected in Table 4 are i) MeCN generally favors b-lactam
formation with high yields and avoids the formation of the cyclo-b-dipeptide, ii) MeCN
also favors b-lactam formation in cases where cyclo-b-dipeptide is generated in lower
yields (Entry 2), and iii) the yield of the cyclo-b-dipeptide is slightly higher when
PhPOCl2 is used.
3. Conclusions. – Several b-amino acids were prepared and evaluated, by using
PhPOCl2, to form b-lactams or cyclo-b-dipeptides. N-Substituted b-amino acids have
the tendency to form cyclo-b-dipeptides, while b3-substituted amino acids form b-
lactams under reaction conditions indicated in Table 1, Entry 3. However, it was
possible to obtain a cyclo-b-dipeptide starting from amino acid 21 (Fig. 4).

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Helvetica Chimica Acta – Vol. 95 (2012)
From N-substituted, b-amino acids, it is possible to obtain either b-lactams or cyclo-
b-dipeptides, or even a mixture of both just by changing the solvent used, when the
Mukaiyamaꢃs reagent is used, benzene favors cyclo-b-dipeptide formation, whereas
MeCN affords b-lactam. Moreover, the yields achieved were slightly higher when
MeCN is used; however, this solvent seemed to have no effect on the reaction of b3-
substituted amino acids.
Experimental Part
General. b3-Amino acids were prepared according to the Rodionov synthesis [24a], and N-alkylation
of b3-amino acids and b-alanine derivatives were conducted by the reductive amination method
developed by Simpkins and co-workers [24b]. All chemicals used for the synthesis of b-amino acids were
obtained commercially (Aldrich) and used without further purification. Solvents were dried using
standard techniques. Reactions were monitored by TLC on Al plates coated with silica gel with
fluorescent indicator (60 F254). Column chromatography (CC) was performed on silica gel (70 – 230 and
230 – 400 mesh). The reactions with microwaves were carried out in Discover CEM equipment. IR
Spectra: Perkin-Elmer FT-IR Spectrum One; ˜nmax in cmꢀ1. NMR Spectra: Varian Gemini at 200 (1H) and
50 MHz (13C), with CDCl3 as solvent, unless stared otherwise; d in ppm rel. to Me4Si as internal standard,
J in Hz. HR-MS: MStation JMS-700 JEOL apparatus; in m/z. The X-ray structures were obtained using
APEX-Brucker apparatus.
General Procedure for the Cyclization of N-Substituted b-Amino Acids. Into a 100-ml flask provided
with magnetic stirrer, the N-substituted b-amino acid (1 mmol) and benzene (40 ml) were placed. Under
N2, Et3N (2 mmol) and PhPOCl2 (1.5 mmol) were added. The mixture was placed in a Discover CEM
equipment at 908 and 130 W during 30 min. After completion, H2O (5 ml) was added, and the mixture
was concentrated in a rotatory evaporator. Extractions with AcOEt (3 ꢁ 10 ml) were carried out, and
after evaporation the crude was purified by CC (silica gel; hexane/AcOEt, 9 :1 ! 5 :5) to yield the
products.
1,5-Dibenzyl-1,5-diazocane-2,6-dione (2A). Yield: 30%. IR: 1633 (C¼O). 1H-NMR: 2.95 (t, 3J ¼ 7.4,
3
2 H); 3.54 (t, J ¼ 6.6, 2 H); 4.6 (s, 2 H); 7.28 (m, 5 H). 13C-NMR: 36.5; 42.2; 49.1; 127.8; 128.4; 128.8;
136.9; 170.2. FAB-MS: 323 ([M þ H]þ). HR-FAB-MS: 322.1700 (Mþ, C20H22N2Oþ2 ; calc. 322.1681).
Spectroscopic data were compared with those reported in [18].
1-Benzylazetidin-2-one (2B). Yield: 11%. IR: 1728 (C¼O). 1H-NMR: 2.95 (t, 3J ¼ 4.0, 2 H); 3.14 (t,
3J ¼ 4.0, 2 H); 4.37 (s, 2 H); 7.31 (m, 5 H). 13C-NMR: 37.0; 38.7; 46.4; 127.8; 128.2; 128.9; 135.7; 167.7.
FAB-MS: 162 ([M þ H]þ). Spectroscopic data were compared with those reported in [25].
1,5-Bis(2,2-dimethylpropyl)-1,5-diazocane-2,6-dione (5A). Yield: 25%. IR: 1641 (C¼O). 1H-NMR:
3
3
0.91 (s, 9 H); 2.94 (t, J ¼ 7.4, 2 H); 3.15 (s, 2 H); 3.71 (t, J ¼ 7.4, 2 H). 13C-NMR: 28.5; 34.2; 37.0; 46.0;
58.0; 171.1. FAB-MS: 283 ([M þ H]þ). HR-FAB-MS: 283.2389 ([M þ H]þ, C16H31N2Oþ2 ; calc. 283.2386).
1
1-(2,2-Dimethylpropyl)azetidin-2-one (5B). Yield: 64%. IR: 1738 (C¼O). H-NMR: 0.86 (s, 9 H);
2.86 (s, 2 H); 2.87 (t, 3J ¼ 4.4, 2 H); 3.26 (t, 3J ¼ 4.0, 2 H). 13C-NMR: 27.9; 33.2; 37.0; 42.3; 54.7; 168.4. HR-
FAB-MS: 142.1244 ([M þ H]þ, C8H16NOþ; calc. 142.1232).
1,5-Bis(cyclohexylmethyl)-1,5-diazocane-2,6-dione (6A). Yield: 28%. IR: 1632 (C¼O). 1H-NMR:
0.90 (m, 6 H); 1.22 (br., 6 H); 1.63 (br., 10 H); 2.91 (t, 3J ¼ 7.0, 4 H); 3.17 (d, 3J ¼ 6.6, 4 H); 3.61 (t, 3J ¼
6.6, 4 H). 13C-NMR: 14.5; 26.1; 26.6; 31.1; 36.9; 37.3; 44.5; 53.2; 170.3. FAB-MS: 335 ([M þ H]þ). HR-
FAB-MS: 335.2684 ([M þ H]þ, C20H35N2O2þ ; calc. 335.2699).
1
1-(Cyclohexylmethyl)azetidin-2-one (6B). Yield: 48%. IR: 1738 (C¼O). H-NMR: 0.96 (br., 2 H);
1.22 (br., 3 H); 1.71 (br., 6 H); 2.93 (t, 3J ¼ 4.4, 2 H); 3.03 (d, 3J ¼ 7.0, 2 H); 3.26 (t, 3J ¼ 4.0, 2 H).
13C-NMR: 25.7; 26.2; 30.9; 36.5; 36.6; 39.9; 48.5; 167.7. HR-FAB-MS: 168.1407 ([M þ H]þ, C10H18NOþ;
calc. 168.1388).
(ꢂ)-4-Methyl-1-pentylazetidin-2-one (27B). Yield: 65%. IR: 1736 (C¼O). 1H-NMR: 0.89 (t, 3J ¼ 6.0,
3 H); 1.34 (d, 3J ¼ 6.2, 9 H); 1.53 (t, 3J ¼ 7.0, 2 H); 2.47 (d, Jgem ¼ 14.3, 3J ¼ 1.6, 1 H); 3.01 (m, 2 H); 3.30
(m, 1 H); 3.66 (m, 1 H). 13C-NMR: 14.1; 18.8; 22.4; 27.9; 29.4; 40.4; 43.8; 47.3; 167.0. FAB-MS: 156 ([M þ
H]þ). HR-FAB-MS: 156.1370 ([M þ H]þ, C9H18NOþ; calc. 156.1388).

Helvetica Chimica Acta – Vol. 95 (2012)
2227
1
(ꢂ)-4-Methyl-1-(3-methylbutyl)azetidin-2-one (28B). Yield: 64%. IR: 1738 (C¼O). H-NMR: 0.91
3
3
3
(d, J ¼ 3.6, 3 H); 0.94 (d, J ¼ 3.2, 3 H); 1.33 (m, 3 H); 1.43 (m, 2 H); 1.52 (m, 1 H); 2.47 (dd, J ¼ 2.0,
Jgem ¼ 14.3, 1 H); 3.03 (m, 2 H); 3.34 (m, H); 3.66 (m, 1 H). 13C-NMR: 18.9; 22.5; 22.6; 26.1; 36.9; 38.7;
43.9; 47.3; 166.9. EI-MS: 155 (Mþ).
(ꢂ)-1-(2,2-Dimethylpropyl)-4-methylazetidin-2-one (29B). Yield: 65%. IR: 1737 (C¼O). 1H-NMR:
3
3
0.87 (s, 9 H); 1.24 (d, J ¼ 6.2, 3 H); 2.41 (dd, J ¼ 1.8, Jgem ¼ 15, 1 H); 2.49 (d, Jgem ¼ 15, 1 H); 3.04 (dd,
3J ¼ 4.8, Jgem ¼ 14.2, 1 H); 3.16 (d, Jgem ¼ 14.4, 1 H); 3.71 (m, 1 H). 13C-NMR: 18.0; 28.1; 32.3; 44.2; 49.4;
51.8; 167.8. EI-MS: 155 (Mþ).
1
(ꢂ)-1-(Cyclohexylmethyl)-4-methylazetidin-2-one (30B). Yield: 55%. IR: 1737 (C¼O). H-NMR:
0.95 (m, 3 H); 1.21 (br., 2 H); 1.31 (d, 3J ¼ 6.2, 3 H); 1.61 (br., 6 H); 2.47 (dd, 3J ¼ 2.2, Jgem ¼ 14.2 H, 1 H);
2.78 (dd, 3J ¼ 6.2, Jgem ¼ 13.8, 1 H); 3.05 (dd, 3J ¼ 3.8, Jgem ¼ 14.4, 1 H); 3.15 (dd, 3J ¼ 7.8, Jgem ¼ 14.4, 1 H);
3.64 (m, 1 H). 13C-NMR: 18.5; 25.8; 25.8; 26.4; 31.1; 31.2; 37.0; 43.8; 46.7; 47.9; 167.1. FAB-MS: 182
([M þ H]þ). HR-FAB-MS: 182.1532 ([M þ H]þ, C11H20NOþ; calc. 182.1545).
1
3
(ꢂ)-1-Benzyl-4-methylazetidin-2-one (31B). Yield: 69%. IR: 1730 (C¼O). H-NMR: 1.20 (d, J ¼
3
3
6.2, 3 H); 2.52 (dd, J ¼ 1.4, Jgem ¼ 14.2, 1 H); 3.05 (dd, J ¼ 5, Jgem ¼ 14.6, 1 H); 3.57 (m,1 H); 4.10 (d,
Jgem ¼ 15.4, 1 H); 4.57 (d, Jgem ¼ 15.4, 1 H); 7.3 (m, 5 H). 13C-NMR: 18.5; 44.1; 44.3; 47.1; 127.5; 128.1;
128.6; 136.0; 166.7. FAB-MS: 176 ([M þ H]þ). HR-FAB-MS: 176.1093 ([M þ H]þ, C11H14NOþ; calc.
176.1075). Spectroscopic data were compared with those reported in [25][26].
(ꢂ)-4-(tert-Butyl)-1-pentylazetidin-2-one (32B). Yield: 86%. IR: 1746 (C¼O). 1H-NMR: 0.76 (t,
3J ¼ 7.0, 3 H); 0.82 (s, 9 H); 1.16 (m, 4 H); 1.43 (m, 2 H); 2.43 (dd, 3J ¼ 2.0, Jgem ¼ 14.8, 1 H); 2.64 (dd, 3J ¼
5.2, Jgem ¼ 14.6, 1 H); 2.80 (m, 1 H); 3.28 (m, 1 H); 3.41 (m, 1 H). 13C-NMR: 13.9; 22.2; 25.8; 27.2; 29.1;
32.7; 37.8; 42.2; 60.3; 167.8. HR-FAB-MS: 198.1856 ([M þ H]þ, C12H24NOþ; calc. 198.1858).
1
(ꢂ)-4-(tert-Butyl)-1-(3-methylbutyl)azetidin-2-one (33B). Yield: 65%. IR: 1744 (C¼O). H-NMR:
0.91 (d, 3J ¼ 6.4, 6 H); 0.95 (s, 9 H); 1.47 (m, 3 H); 2.57 (dd, 3J ¼ 1.4, Jgem ¼ 14.6, 1 H); 2.77 (dd, 3J ¼ 5.2,
3
3
3
3
Jgem ¼ 14.6, 1 H); 2.93 (dt, J ¼ 7, Jgem ¼ 14, 1 H); 3.41 (dd, J1 ¼ 2.6, J2 ¼ 5.2); 3.58 (dt, J ¼ 7.6, Jgem
¼
13.8). 13C-NMR: 22.2; 22.6; 25.9; 25.9; 32.8; 36.2; 37.9; 40.6; 60.3; 168.0. FAB-MS: 198 ([M þ H]þ).
HR-FAB-MS: 198.1887 ([M þ H]þ, C12H24NOþ; calc. 198.1858).
(ꢂ)-4-(tert-Butyl)-1-(2,2-dimethylpropyl)azetidin-2-one (34B). Yield: 70%. IR: 1725 (C¼O).
1H-NMR: 0.91 (d, 18 H); 2.48 (dd, J ¼ 2.2, Jgem ¼ 14.6); 2.61 (d, Jgem ¼ 14.6); 2.81 (dd, J ¼ 5.2, Jgem
¼
3
3
15); 3.43 (d, Jgem ¼ 14.4); 3.57 (dd, J1 ¼ 2.2, J2 ¼ 5). 13C-NMR: 26.5; 28.6; 33.4; 34.6; 38.6; 53.5; 62.9;
168.5. FAB-MS: 198 ([M þ H]þ). HR-FAB-MS: 198.1854 ([M þ H]þ, C12H24NOþ; calc. 198.1858).
(ꢂ)-4-(tert-Butyl)-1-(cyclohexylmethyl)azetidin-2-one (35B). Yield: 90%. IR: 1745 (C¼O).
3
3
1H-NMR (400 MHz, CDCl3): 0.95 (s, 11 H); 1.21 (m, 3 H); 1.69 (m, 7 H); 2.58 (dd, J ¼ 2, Jgem ¼ 14.8,
3
1 H); 2.79 (m, 2 H); 3.36 (dd, 3J ¼ 5.6, Jgem ¼ 14.4, 1 H); 3.41 (dd, 3J1 ¼ 2.8, 3J2 ¼ 5.2, 1 H). 13C-NMR
(100 MHz, CDCl3): 25.8; 25.9; 26.0; 26.4; 30.9; 31.2; 32.9; 36.3; 38.0; 48.9; 61.1; 168.5. FAB-MS: 224
([M þ H]þ). HR-FAB-MS: 224.2012 ([M þ H]þ, C14H26NOþ; calc. 224.2014).
(ꢂ)-1-Benzyl-4-(tert-butyl)azetidin-2-one (36B). Yield: 53%. IR: 1740 (C¼O). 1H-NMR: 0.88 (s,
9 H); 2.66 (dd, 3J ¼ 2.5, Jgem ¼ 15, 1 H); 2.82 (dd, 3J ¼ 5.2, Jgem ¼ 14.6, 1 H); 3.3 (dd, 3J1 ¼ 2.8, 3J2 ¼ 5, 1 H);
4.04 (d, Jgem ¼ 15.4, 1 H); 4.82 (d, Jgem ¼ 15.4); 7.28 (m, 5 H). 13C-NMR: 26.0; 32.7; 38.4; 46.5; 60.5; 127.6;
128.3; 128.7; 136.2; 168.5. FAB-MS: 218 ([M þ H]þ). HR-FAB-MS: 218.1551 ([M þ H]þ, C14H20NOþ;
calc. 218.1545).
(ꢂ)-4-Cyclohexyl-1-pentylazetidin-2-one (37B). Yield: 76%. IR: 1742 (C¼O). 1H-NMR: 0.89 (t,
3J ¼ 6.6, 3 H); 1.06 (m, 2 H); 1.25 (m, 7 H); 1.59 (m, 8 H); 2.59 (dd, 3J ¼ 2, Jgem ¼ 14.8, 1 H); 2.82 (dd, 3J ¼
5.2, Jgem ¼ 14.2, 1 H); 2.96 (dd, 3J ¼ 6.6, Jgem ¼ 13.6, 1 H); 3.42 (m, 2 H). 13C-NMR: 14.1; 22.4; 25.9; 26.0;
26.4; 27.6; 27.7; 29.3; 30.0; 38.9; 40.4; 41.6; 56.0; 167.7. FAB-MS: 224 ([M þ H]þ). HR-FAB-MS: 224.2012
([M þ H]þ, C14H26NOþ; calc. 224.2014).
1
(ꢂ)-4-Cyclohexyl-1-(3-methylbutyl)azetidin-2-one (38B). Yield: 81%. IR: 1742 (C¼O). H-NMR:
0.79 (d, 3J ¼ 6.4, 6 H); 0.99 (m, 5 H); 1.47 (m, 9 H); 2.45 (dd, 3J ¼ 2.2, Jgem ¼ 14.6, 1 H); 2.68 (dd, 3J ¼ 5.2,
Jgem ¼ 14.6, 1 H); 2.82 (m, 1 H); 3.32 (m, 2 H). 13C-NMR: 21.9; 22.2; 25.5; 25.6; 26.2; 27.2; 29.5; 36.2; 38.5;
39.4; 40.0; 55.5; 167.0. FAB-MS: 224 ([M þ H]þ). HR-FAB-MS: 224.2029 ([M þ H]þ, C14H26NOþ; calc.
224.2014).
(ꢂ)-4-Cyclohexyl-1-(2,2-dimethylpropyl)azetidin-2-one (39B). Yield: 56%. IR: 1753 (C¼O).
1H-NMR: 0.95 (s, 9 H); 1.07 (m, 2 H); 1.28 (m, 3 H); 1.67 (m, 6 H); 2.56 (d, Jgem ¼ 14.2, 1 H); 2.63

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Helvetica Chimica Acta – Vol. 95 (2012)
(dd, 3J ¼ 2.2, Jgem ¼ 14.3, 1 H); 2.88 (dd, 3J ¼ 5.2, Jgem ¼ 14, 1 H); 3.35 (d, Jgem ¼ 14.4, 1 H); 3.64 (m, 1 H).
13C-NMR: 25.9; 26.3; 26.5; 26.6; 28.3; 29.9; 33.9; 38.5; 38.5; 52.5; 58.1; 168.2. FAB-MS: 224 ([M þ H]þ).
HR-FAB-MS: 224.2000 ([M þ H]þ, C14H26NOþ; calc. 224.2014).
(ꢂ)-4-Cyclohexyl-1-(cyclohexylmethyl)azetidin-2-one (40B). Yield: 64%. IR: 1739 (C¼O).
1H-NMR: 0.98 (m, 4 H); 1.21 (m, 7 H); 1.68 (m, 11 H); 2.61 (dd, 3J ¼ 1.8, Jgem ¼ 14, 1 H); 2.79 (m,
2 H); 3.30 (dd, 3J ¼ 8.4, 14.2, 1 H); 3.42 (m, 1 H). 13C-NMR: 25.9; 25.9; 26.1; 26.5; 27.6; 30.0; 31.1; 31.4;
36.8; 38.9; 40.1; 47.9; 56.7; 167.9. FAB-MS: 250 ([M þ H]þ). HR-FAB-MS: 250.2187 ([M þ H]þ,
C16H28NOþ; calc. 250.2171).
(ꢂ)-1,5-Dibenzyl-4,8-dicyclohexyl-1,5-diazocane-2,6-dione (41A). The crystal of this compound was
isolated from the recrystallization of 41B. In 1H- and 13C-NMR only one compound was detected (also
GC-MS and TLC). IR: 1628 (C¼O). FAB-MS: 487 ([M þ H]þ). HR-FAB-MS: 487.3282 ([M þ H]þ,
C32H43N2Oþ2 ; calc. 487.3325).
1
(ꢂ)-1-Benzyl-4-cyclohexylazetidin-2-one (41B). Yield: 72%. IR: 1741 (C¼O). H-NMR: 1.03 (m,
5 H); 1.55 (m, 6 H); 2.66 (dd, 3J ¼ 2.8, Jgem ¼ 14.6, 1 H); 2.86 (dd, 3J ¼ 5, Jgem ¼ 14.4, 1 H); 3.29 (m, 1 H);
4.05 (d, Jgem ¼ 15, 1 H); 4.73 (d, Jgem ¼ 15, 1 H); 7.31 (m, 5 H). 13C-NMR: 25.9; 26.0; 26.4; 27.6; 30.0; 39.5;
40.3; 45.8; 55.9; 127.7; 128.3; 128.4; 128.8; 136.2; 167.9; 191.8. FAB-MS: 244 ([M þ H]þ). HR-FAB-MS:
244.1729 ([M þ H]þ, C16H22NOþ; calc. 244.1701).
(ꢂ)-1-Pentyl-4-phenylazetidin-2-one (42B). Yield: 18%. IR: 1753 (C¼O). 1H-NMR: 0.85 (t, J ¼ 6.6,
3 H); 1.24 (m, 3 H); 1.45 (m, 3 H); 2.81 (m, 2 H); 3.38 (m, 2 H); 4.55 (dd, 3J1 ¼ 2.6, 3J2 ¼ 5.2, 1 H); 7.30
(m, 5 H). 13C-NMR: 14.2; 22.4; 27.6; 29.7; 41.0; 46.9; 54.3; 126.5; 128.6; 129.1; 138.6; 167.5. CI-MS: 218
([M þ H]þ). HR-CI-MS: 218.1543 ([M þ H]þ, C14H20NOþ; calc. 218.1545).
1
(ꢂ)-1-(3-Methylbutyl)-4-phenylazetidin-2-one (43B). Yield: 62%. IR: 1753 (C¼O). H-NMR: 0.83
(d, J ¼ 3.0, 3 H); 0.86 (d, J ¼ 3.0, 3 H); 1.47 (m, 3 H); 2.81 (m, 2 H); 3.35 (dd, 3J ¼ 5.0, Jgem ¼ 14.2, 1 H);
3.48 (dd, 3J ¼ 8.0, Jgem ¼ 14.2, 1 H); 4.53 (dd, 3J1 ¼ 2.2, 3J2 ¼ 5.2, 1 H); 7.35 (m, 5 H). 13C-NMR: 22.4; 22.6;
26.1; 36.5; 26.1; 36.5; 39.4; 46.9; 54.3; 126.5; 128.6; 129.1; 138.6; 167.5. CI-MS: 218 ([M þ H]þ). HR-CI-
MS: 218.1529 ([M þ H]þ, C14H20NOþ; calc. 218.1545).
(ꢂ)-1-(2,2-Dimethylpropyl)-4-phenylazetidin-2-one (44B). Yield: 20%. IR: 1629 (C¼O). 1H-NMR:
0.87 (s, 9 H); 2.28 (d, Jgem ¼ 14.2, 1 H); 2.79 (d, Jgem ¼ 14.8, 1 H); 3.37 (m, 2 H); 4.62 (m, 1 H); 7.32 (m,
5 H). 13C-NMR: 28.1; 33.4; 47.1; 52.3; 56.9; 126.7; 128.6; 129.0; 137.8; 168.2. CI-MS: 218 ([M þ H]þ). HR-
CI-MS: 218.1557 ([M þ H]þ, C14H20NOþ; calc. 218.1545).
1
(ꢂ)-1-(Cyclohexylmethyl)-4-phenylazetidin-2-one (45B). Yield: 52%. IR: 1751 (C¼O). H-NMR:
1.28 (m, 11 H); 2.58 (dd, 3J ¼ 6.0, Jgem ¼ 14.0, 1 H); 2.81 (dd, 3J ¼ 2.0, Jgem ¼ 14.8, 1 H); 3.28 (dd, 3J ¼ 7.6,
3
3
3
Jgem ¼ 13.8, 1 H); 3.38 (dd, J ¼ 5.2, Jgem ¼ 14.6, 1 H); 2.55 (dd, J1 ¼ 2.2, J2 ¼ 5.2, 1 H); 7.36 (m, 5 H).
13C-NMR: 25.8; 26.4; 31.1; 31.2; 36.8; 46.9; 47.2; 55.1; 126.5; 128.6; 129.0; 138.4; 167.7. CI-MS: 244 ([M þ
H]þ). HR-CI-MS: 244.1669 ([M þ H]þ, C16H22NOþ; calc. 244.1701).
(ꢂ)-1-Benzyl-4-phenylazetidin-2-one (46B). Yield: 50%. IR: 1751 (C¼O). 1H-NMR: 2.87 (dd, 3J ¼
1.4, Jgem ¼ 14.6, 1 H); 3.35 (dd, 3J ¼ 5.2, Jgem ¼ 14.6, 1 H); 3.76 (d, Jgem ¼ 14.8, 1 H); 4.40 (dd, 3J1 ¼ 2.2, 3J2 ¼
5.2, 1 H); 4.81 (d, Jgem ¼ 15.2, 1 H); 7.29 (m, 10 H). 13C-NMR: 45.0; 47.1; 53.8; 126.7; 127.8; 128.7; 128.9;
129.1; 135.7; 138.0; 167.3. CI-MS: 238 ([M þ H]þ). HR-CI-MS: 238.1230 ([M þ H]þ, C16H16NOþ; calc.
238.1232). Spectroscopic data were compared with those reported in [18][26].
We would like to thank Dr. Gaurau Tibhe for his suggestions, also we are grateful to CONACYT for
financial support (Project CB2010/151875) and for scholarships to L. G. H.-V.
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Received August 10, 2012